Research

We are broadly interested in understanding atomic-scale mechanisms of how membrane proteins function under normal and diseased states. Membrane proteins play critical roles in nearly every aspect of physiological processes that encompass relaying signals between cells, transporting small molecules and ions across the membrane and catalyzing vital enzymatic reactions. Importantly, membrane proteins constitute ~60% of targets of currently approved drugs and thus in-depth knowledge about their inner workings is sorely needed to inform the development of effective therapeutic strategies for treating various human diseases.

Our current research program focuses on structure and function of receptors, transporters, and ion channels that are implicated in kidney diseases. In particular, we are studying polycystic kidney disease proteins PKD1 and PKD2, which are sites of mutation of a widespread genetic disorder ADPKD that affects 600,000 Americans and 12.5 million patients worldwide. Moreover, we are also interested in developing pharmacological tools (e.g. small chemical compounds, peptide toxins, and antibodies) for probing function of ion channels and receptors. Importantly, such molecules are also important leads that can potentially evolve into drugs for treating patients with PKD. We are also investigating structures and pharmacology of cation-chloride cotransporters (CCCs). Several CCCs play a vital role in water and salt retention in the kidney and they are molecular targets of loop and thiazide diuretics that are widely prescribed for the treatment of hypertension and edema. To achieve these goals, we employ a multidisciplinary approach that includes molecular biology, protein biochemistry, pharmacology, ion channel electrophysiological, and X-ray crystallography and single- particle electron cryo-microscopy.